Induced Pluripotent Stem Cells for Cardiovascular Disease Modeling and Precision Medicine: A Scientific Statement From the American Heart Association

Abstract

Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to study human physiology and disease at the cellular level. They also have the potential to be leveraged in the practice of precision medicine, for example, personalized drug testing. This statement comprehensively describes the provenance of iPSC lines, their use for cardiovascular disease modeling, their use for precision medicine, and strategies through which to promote their wider use for biomedical applications. Human iPSCs exhibit properties that render them uniquely qualified as model systems for studying human diseases: they are of human origin, which means they carry human genomes; they are pluripotent, which means that in principle, they can be differentiated into any of the human body’s somatic cell types; and they are stem cells, which means they can be expanded from a single cell into millions or even billions of cell progeny. iPSCs offer the opportunity to study cells that are genetically matched to individual patients, and genome-editing tools allow introduction or correction of genetic variants. Initial progress has been made in using iPSCs to better understand cardiomyopathies, rhythm disorders, valvular and vascular disorders, and metabolic risk factors for ischemic heart disease. This promising work is still in its infancy. Similarly, iPSCs are only just starting to be used to identify the optimal medications to be used in patients from whom the cells were derived. This statement is intended to (1) summarize the state of the science with respect to the use of iPSCs for modeling of cardiovascular traits and disorders and for therapeutic screening; (2) identify opportunities and challenges in the use of iPSCs for disease modeling and precision medicine; and (3) outline strategies that will facilitate the use of iPSCs for biomedical applications. This statement is not intended to address the use of stem cells as regenerative therapy, such as transplantation into the body to treat ischemic heart disease or heart failure.

Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes in Familial Dilated Cardiomyopathy

“…We used human hPSC-CMs to study how the initial insult of a molecular-based change leads to the early disease pathogenesis in human cells. For these studies, hPSC-CMs are excellent models, since they can capture cellular changes that occur before major compensatory mechanisms (e.g., fibrosis, activation of neurohormonal pathways, changes in gene expression) mask the initial molecular phenotype (18–20, 54, 72). Contractile changes associated with the disease have been observed in cardiomyopathy patients before adverse remodeling of the heart (73–75).…”

“…Recent advances in stem cell (15, 16) and gene editing technologies (17) have provided a new avenue for modeling DCM in human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) (18, 19). These hPSC-CMs can faithfully recapitulate many aspects of the early human disease (20), making them an excellent tool for deciphering how the initial molecular insult leads to the development of the early disease phenotype. Moreover, these cells can be examined in simplified in vitro systems that mimic various aspects of the environment in the heart to dissect how the local environment influences the development of the disease phenotype.…”

Secretome Analysis Performed During in vitro Cardiac Differentiation: Discovering the Cardiac Microenvironment

“…In vitro cardiomyogenic differentiation of human embryonic (hESC) or induced pluripotent stem cells (hiPSCs) is an alternative to modeling two basic research studies: (a) enables the study of cardiomyogenesis process, cardiac disease modeling, and development of cardiotoxicity tests, and (b) can be used in cell therapy protocols, thereby generating specific cell populations, e.g., cardiomyocytes for tissue replacement (Murry and Keller, 2008;Van Vliet et al, 2012;Musunuru et al, 2018). The commitment to the cardiac lineage during embryonic development includes several steps that are regulated by a network of transcription factors and signaling pathways that control the specification and maturation of cardiac cells (Olson, 2006;Van Vliet et al, 2012).…”

Inherited cardiac diseases, pluripotent stem cells, and genome editing combined—the past, present, and future

“…Furthermore, many nongenetic factors can influence the behavior and phenotype of the hiPSC-CMs, including different reprogramming methodologies, the epigenetic profiles of the hiPSC lines, and potential to differentiate into the desired cell type. 61 To reduce these effects, most hiPSC cardiac disease modeling studies have focused on patients with highly penetrant monogenic diseases and a clear autosomal dominant inheritance pattern, meaning the severity of the disease phenotype will generally outweigh any noise caused by confounding factors from the control line. But this does not demonstrate that the phenotype is directly or solely caused by the suspected mutation(s).…”